This invention is drawn to the organic synthesis of nucleosides, and in particular relates to a highly stereoselective process for the preparation of 3'-substituted-2',3'-dideoxynucleosides and 2'-deoxynucleosides from acyclic, achiral precursors.
In 1985, it was reported that the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus type 1 (referred to below as HIV), the etiological cause of acquired immune deficiency syndrome (AIDS). Since then, a number of other synthetic nucleosides, including 3'-fluoro-3'-deoxythymidine (FLT) and 3'-azido-2',3'-dideoxyuridine (AZDU), have proven to be effective against HIV. A number of other 2',3'-dideoxynucleosides have been demonstrated to inhibit the growth of a variety of other viruses in vitro. It appears that, after cellular phosphorylation to the 5'-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination. 3'-Azido-3'-deoxythymidine is a potent inhibitor of HIV reverse transcriptase and is presently the only drug that has been approved by the FDA for the treatment of AIDS.
2',3'-Dideoxynucleosides have historically been prepared by either of two routes; deoxygenation and derivatization of an intact nucleoside, or condensation of a derivatized sugar moiety with a nitrogenous base.
The original synthesis of 3'-substituted-2',3'-dideoxynucleosides from 2'-deoxynucleosides by Horwitz et al. illustrates the first approach: the modification of intact nucleosides by altering the carbohydrate moiety (see Scheme I below). Horwitz, J. P.; Chua, J.; Noel, M. J. Org. Chem. 29, 2076 (1964); Horwitz, J. P.; Chua, J.; Urbanski, J. A.; Noel, M. J. Org. Chem., 28, 942 (1963); and Horwitz, J. P.; Chua, J.; Urbanski, J. A. J. Org Chem., 27, 3300 (1962). Horwitz prepared AZT by replacement of the 3'-hydroxyl group of thymidine with azide in a four step process with retention of stereochemistry. The advantages of this approach are numerous. It is short, efficient and proceeds with a high degree of stereocontrol. The major disadvantage is that the high cost of the starting material, 2'-deoxynucleoside, makes the overall process expensive. ##STR1##
The second general approach is illustrated by the synthesis of AZT and AZDU, by Chu, et al. Chu, C. K., et al., Tetrahedron Lett., 29, 5349 (1988); U.S. Pat. No. 4,987,224. Starting from D-mannitol, a derivatized ribose is prepared in eight steps, that, when exposed to Vorbruggen coupling conditions with a protected thymidine or uridine followed by deprotection, forms a 1:1 .alpha. to .beta. anomeric mixture of AZT (or AZDU). (See Scheme II below.) ##STR2## The .beta.-anomeric nucleoside is more biologically active than the .alpha.-anomeric nucleoside, and must be isolated from the mixture through a chromatographic separation.
Most of the other reported methods of preparation of nucleosides are suitable only as laboratory syntheses to obtain small amounts of compound for experimental use, but are not well suited for industrial scale preparation of the compounds, because of the number of steps required to obtain the product and or the cost of the nucleoside starting material.
The problems described above that are encountered in the preparation of pharmaceutically active nucleosides increase the public cost of health care and result in shortages of severely needed antiviral compounds. In fact, the high cost of the antiviral, and in particular anti-HIV, nucleosides prevents many of those in need from being able to obtain the drug at all.
Therefore, it is an object of the present invention to provide a synthesis of 3'-substituted-2',3'-dideoxynucleosides and 2'-deoxynucleosides from inexpensive, readily available starting materials.
It is another object of the present invention to provide a synthesis of 3'-substituted-2',3'-dideoxynucleosides and 2'-deoxynucleosides that does not result in the production of a significant amount of undesired isomers or anomers.